This is a revised competitive renewal application of our grant entitled "Ghrelin in Hypothalamic Regulation of Metabolism" (R01 DK-060711-04A1). The original application was planned for 5 years, but was cut to 2 years, 11 months, and the funds requested for each year were then further decreased due to budgetary constraints of NIDDK. Nevertheless, even with this funding and time constraints, we have made progress in the past 2 1/2 years to better understand ghrelin's action within the brain. Of the newly acquired information, there are 2 critical findings which provide the basis for the request for continuation: 1) ghrelin induces synaptic remodeling of the melanocortin system while inducing positive energy balance; 2) peripheral ghrelin administration activates ventral tegmental dopamine neurons elevating dopamine release in the nucleus accumbens, and, ghrelin administration selectively to the ventral tegmental area induces acute food intake. We make 2 inferences from these findings: 1) The action of ghrelin on the output of neuronal circuitry associated with metabolism regulation involves and partially relies on synaptic plasticity, and 2) ghrelin's effect on food intake is greatly augmented by direct activation of the basal forebrain reward circuitry. We propose the following Specific Aims to follow up on these premises: Specific Aim 1) To reveal a) whether circulating ghrelin affects synaptic plasticity in the arcuate nucleus in a dose-dependent manner, b) the time course of synaptic changes to emerge and to diminish after acute ghrelin administration, c) if the circadian fluctuation of the synaptic input organization of POMC neurons is ghrelin dependent, d) the interaction between ghrelin and leptin or corticosterone (CORT) in the acute regulation of synaptic plasticity and feeding, and e) whether ghrelin-induced synaptic plasticity in the arcuate nucleus is impaired in mice with mutations in ghrelin signaling. Specific Aim 2) To determine a) if ghrelin-induced synaptic plasticity also occurs in the major neuronal populations within the ventral tegmental area (VTA). In b) We will examine the role of GHS-R 1a in mediating synaptic changes in VTA neurons. Specific Aim 3) To determine that ghrelin targets the VTA to enhance motivational aspects of feeding and to promote the consumption of calorie rich diets, if the resistance of ghrelin knockout animals to diet-induced obesity is due to ghrelin's inaction upon reward circuitry. The proposed studies will deliver new insights to metabolism regulation, likely revealing novel targets for obesity drug development. [unreadable] [unreadable] [unreadable]